Biology subjects

Nijman, I. J.

Publications and source records attributed to Nijman, I. J..

3 recordsLinked to original sources

bioRxiv2025

Organoid-evaluable clinical biomarkers predict drug responses and guide new breast cancer therapies

Poor therapeutic response in subsets of breast cancer (BC) patients poses an ongoing challenge. Here, we present a biomarker-guided characterization of 44 patient-derived BC organoids, with the aim of modeling resistant disease with greater fidelity and developing an in-vitro system grounded in clinical data for testing alternative treatment strategies. We utilized patient transcriptomic and outcome data from the I-SPY2 clinical trial to develop predictive models of response to a range of therapies, using only organoid-detectable biomarkers as input. A model predicting response to veliparib-platinum chemotherapy (VP) in triple-negative BC (TNBC) was validated in organoids, showing that in vitro drug responses matched predictions from the patient data-derived model. A drug screen in VP-resistant TNBC organoids identified combination treatments that overcame resistance to cisplatin, including pro-apoptotic therapies. This demonstrates that gene expression-based resistance models derived from patient data can be successfully modeled in organoids that can then be used for therapeutic evaluation.

cancer biology↗

bioRxiv2023

Somatic mutation of Afadin leads to anchorage independent survival and metastatic growth of breast cancer through alpha E-catenin dependent destabilization of the adherens junction

Loss of E-cadherin (CDH1) and the adherens junction (AJ) drive development and progression of invasive lobular breast cancer (ILC). However, approximately 40% retain wild type CDH1 alleles, indicating that modulation of other genes attenuates the AJ during ILC etiology. To identify alternative drivers, we performed targeted sequencing in CDH1 wild type samples, based on a defined set of 100 AJ, tight junction, and desmosome genes we designated as the Adhesome. In 146 ILC samples, we identified 62 cases (43%) with wild type CDH1 alleles in which we detected a total of 284 mutations in 36 Adhesome genes. After selection based on occurrence and potential loss of function, we identified an inactivating frameshift mutation in Afadin (AFDN; p.Lys630fs). Functional studies in E-cadherin-expressing breast cancer cells showed that Afadin knockout leads to immature AJs, and a non-cohesive phenotype accompanied by actomyosin dependent anoikis resistance, which are classical ILC hallmarks. Afadin reconstitutions show that F-actin organization critically depends on the E-catenin binding CC domain. Afadin loss in intraductal xenograft mouse breast cancer models leads to ILC-type morphologies and overt lung metastases. AFDN truncate reconstitutions revealed that deletion of the C-terminal E-catenin binding CC domain is sufficient to drive metastatic ILC. In conclusion, we identified and functionally coupled a somatic frameshift AFDN mutation in breast cancer to destabilization the epithelial AJ and the development of ILC hallmarks such as actomyosin-dependent anoikis resistance and single cell invasion. As such, Afadin represents a candidate tumor suppressor for E-cadherin-positive ILC development and progression.

cancer biology↗

bioRxiv2020

Phylogeny and distribution of Y-chromosomal haplotypes in domestic, ancient and wild goats

The male-specific part of the Y-chromosome is in mammalian and many other species the longest haplotype that is inherited without recombination. By its paternal transmission it has a small effective population size in species with dominant males. In several species, Y-chromosomal haplotypes are sensitive markers of population history and introgression. Previous studies have identified in domestic goats four major Y-chromosomal haplotypes Y1A, Y1B, Y2A and Y2B with a marked geographic differentiation and several regional variants. In this study we used published whole-genome sequences of 70 male goats from 16 modern breeds, 11 ancient-DNA samples and 29 samples from seven wild goat species. We identified single-copy male-specific SNPs in four scaffolds, containing SRY, ZFY, DBY with SSX3Y and UTY, and USP9Y with UMN2001, respectively. Phylogenetic analyses indicated haplogroups corresponding to the haplotypes Y1B, Y2A and Y2B, respectively, but Y1A was split into Y1AA and Y1AB. All haplogroups were detected in ancient DNA samples from southeast Europe and, with the exception of Y1AB, in the bezoar goat, which is the wild ancestor of the domestic goats. Combining these data with those of previous studies and with genotypes obtained by Sanger sequencing or the KASP assay yielded haplogroup distributions for 132 domestic breeds or populations. The phylogeographic differentiation indicated paternal population bottlenecks on all three continents. This possibly occurred during the Neolithic introductions of domestic goats to those continents with a particularly strong influence in Europe along the Danubian route. This study illustrates the power of the Y-chromosomal haplotype for the reconstructing the history of mammalian species with a wide geographic range.

genetics↗